The difficulty of synthesizing a diverse array of complex molecules from readily available precursors has led to the development of many elegant and highly specific transformations in efforts to reach desired targets. An alternate approach to generating many specialized transformations focuses instead on using a small pool of highly efficient reactions. The idea of “click chemistry” mimics nature's modular usage of heteroatom linkages to afford a wide variety of macromolecular scaffolds. See H. C. Kolb; M. G. Finn; K. B. Sharpless (2001) “Click Chemistry: Diverse Chemical Function from a Few Good Reactions,” Angewandte Chemie International Edition 40(11):2004-2021. While it is unlikely this approach would completely supplant the traditional strategies of molecular synthesis, the use of “click chemistry” has had notable applications and widespread use. See, for example, R. A. Evans (2007) “The Rise of Azide-Alkyne 1,3-Dipolar ‘Click’ Cycloaddition and its Application to Polymer Science and Surface Modification,” Australian Journal of Chemistry 60(6):384-395; Spiteri, Christian; Moses, John E. (2010) “Copper-Catalyzed Azide-Alkyne Cycloaddition: Regioselective Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles,” Angewandte Chemie International Edition 49(1):31-33; and Hoyle, Charles E.; Bowman, Christopher N. (2010) “Thiol-Ene Click Chemistry,” Angewandte Chemie International Edition 49(9):1540-1573.
In the design and optimization of reactions used in this manner, basic principles of chemical reactivity must be utilized. Whether a cascade reaction leads to a complex natural product (for example, a specialized Diels-Alder cycloadditions employed by Boger) or a simple SN2 displacement, understanding how to manipulate weak bonds in starting compounds and transform them into strong bonds in the products requires the presence of a “driving force.” When the inherent energy profile is not favorable for the desired reaction to go to completion, an extra ‘push’ is often provided by a catalyst. This is the case for arguably the most efficient “click” reaction, the copper-catalyzed azide-alkyne cycloaddition (CuAAC). See, for example, Castro, Rodríguez and Albericio (2016) “CuAAC: An Efficient Click Chemistry Reaction on Solid Phase,” ACS Comb. Sci. 18(1):1-14. While CuAAC is undoubtedly an incredibly valuable transformation with broad applications, limitations do exist which are often linked to the requirement for this catalyst.
In place of a catalyst, one highly effective strategy to promote reactivity has been the use of the release of strain energy. See FIG. 1, panels A, B, and C. However, incorporating strained alkynes into the starting compounds can increase reactivity of the alkyne bond to the point that is extremely difficult to isolate the starting compound. In fact, early attempts required a cycloaddition reaction to trap the intermediate cyclooctynes in order to prove their generation in situ. Since these early reports of strain as a method to increase reactivity, there has been intense interest in these unique molecules that was further renewed when strain was applied to azide-alkyne cycloadditions (strain-promoted azide-alkyne cycloadditions, SPAAC). See, for example, Baskin, J. M.; Bertozzi, C. R. (2007) “Bioorthogonal Click Chemistry: Covalent Labeling in Living Systems,” QSAR Comb. Sci. 26:1211-1219; Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. (2008) “Second-Generation Difluorinated Cyclooctynes for Copper-Free Click Chemistry,” J. Am. Chem. Soc. 130:11486-11493; Johnson, J. A.; Baskin, J. M.; Bertozzi, C. R.; Koberstein, J. T.; Turro, N. J. (2008) “Copper-free click chemistry for the in situ crosslinking of photodegradable star polymers,” Chem. Commun. 3064-3066; and Sletten, E. M.; Bertozzi, C. R. (2008) “A Hydrophilic Azacyclooctyne for Cu-Free Click Chemistry,” Org. Lett. 10:3097-3099.
The strain energy present in various cycloalkynes was used by Bertozzi and co-workers, supra, to sidestep the cytotoxicity associated with CuAAC by eliminating the need for copper catalysts, which proved problematic when attempting to use Huisgen 1,3-dipolar reactions in vivo. Since this initial report, new cyclic alkynes have been reported, with properties expanding the utility of this chemistry. These types of reactions are used in various fields, including biological labeling, the synthesis of specialized polymers and ligands, and the generation of libraries of medicinally relevant compounds.
The value of cycloalkynes is due, in part, to their fast rates of reaction. As a result, several strategies have been explored to increase their reactivity in a predictable and controllable manner. The most common approach involves “ring strain activation,” where cyclopropanes, aryl groups or other sites of unsaturation are introduced into the molecule providing for rate enhancement of >2 orders of magnitude. Examples include the compounds known by their trivial names as bicyclo[6.1.0]nonyne (“BCN”), dibenzocyclooctynone (“DIBONE”), and dibenzoazacyclooctyne (“DIBAC”):

However, this strategy can be problematic, as these changes result in inherent destabilization of the ring. Cycloalkynes activated primarily by increased strain may become sensitive to heat or light, they require harsh conditions to prepare, and typically have a very short shelf life.
A different tactic to increase reactivity is achieved by manipulation of the desired reaction's transition state through electronic stabilization, in addition to the typical ring strain. See FIG. 1, panels A and B. This allows for an increase in reactivity over alkynes which rely solely on strain activation without sacrificing stability of the alkyne. In addition to raising the reactivity of the alkyne, combining electronic activation with strain offers the possibility of tuning each alkyne to a distinct coupling partner. Theoretically, this should yield alkynes with both fast reaction rates and selective reactivity.
The most successful previous efforts to combine strain and electronic effects take advantage of the increased reactivity provided by electronegative atoms at the propargylic position. Again, see FIG. 1 at panels A and B. It has been shown that rate enhancements which stem from hyperconjugative π→σ*C—X interactions are especially important contributors in the transition state (TS). When σ-acceptors are also contained within the cyclic framework, they allow for strengthened hyper-conjugative (π→σ*C—X) interactions relative to systems containing exocyclic σ-acceptors. This is a result of the orientation of the endocyclic propargylic atom(s), which lie antiperiplanar relative to the new bonds being formed. See FIG. 1, panel B. When the σ-acceptor is located in an endocyclic orientation, it is already positioned appropriately for maximal electronic interaction in the transition state. This is in contrast to the gauche orientation noted when the propargylic σ-acceptors are exocyclic, as the propargylic C—C bond of the ring precludes them from adopting the ideal antiperiplanar geometry. Tomooka and co-workers recently synthesized medium-sized cycloalkynes with heteroatoms embedded at the propargylic positions that enable cycloaddition rates faster than those of cyclooctyne (“OCT”) and monofluorinated cyclooctyne (“MOFO”), but do not yet surpass those of difluorocyclooctyne (DIFO). See Ni, Mitsuda, Kashiwagi, Igawa, and Tomooka (2015) “Heteroatom-embedded Medium-Sized Cycloalkynes: Concise Synthesis, Structural Analysis, and Reactions,” Angewandte Chemie International 54(4):1190-1194.
Although many impressive strained alkynes have been reported, the existing chemistry remains far from optimal. There is an ongoing and unmet need for new strained cycloalkynes that offer ease and flexibility in synthesis, chemoselectivity, and reduced lipophilicity.